1. Field of the Invention
The present invention relates generally to the combinatorial synthesis of bicyclic guanidine derivatives. More specifically, the invention provides novel bicyclic guanidines as well as novel combinatorial libraries comprised of many such compounds, and methods of synthesizing the libraries.
2. Background Information
The process of discovering new therapeutically active compounds for a given indication involves the screening of all compounds from available compound collections. From the compounds tested one or more structure(s) is selected as a promising lead. A large number of related analogs are then synthesized in order to develop a structure-activity relationship and select one or more optimal compounds. With traditional one-at-a-time synthesis and biological testing of analogs, this optimization process is long and labor intensive. Adding significant numbers of new structures to the compound collections used in the initial screening step of the discovery and optimization process cannot be accomplished with traditional one-at-a-time synthesis methods, except over a time frame of months or even years. Faster methods are needed that allow for the preparation of up to thousands of related compounds in a matter of days or a few weeks. This need is particularly evident when it comes to synthesizing more complex compounds, such as the bicyclic guanidine compounds of the present invention.
Solid-phase techniques for the synthesis of peptides have been extensively developed and combinatorial libraries of peptides have been generated with great success. During the past four years there has been substantial development of chemically synthesized combinatorial libraries (SCLs) made up of peptides. The preparation and use of synthetic peptide combinatorial libraries has been described, for example, by Dooley in U.S. Pat. No. 5,367,053, Huebner in U.S. Pat. No. 5,182,366, Appel et al. in WO PCT 92/09300, Geysen in published European Patent Application 0 138 855 and Pirrung in U.S. Pat. No. 5,143,854. Such SCLs provide the efficient synthesis of an extraordinary number of various peptides in such combinatorial libraries and the rapid screening of the library which identifies lead pharmaceutical peptides.
Peptides have been, and remain, attractive targets for drug discovery. Their high affinities and specificities toward biological receptors as well as the ease with which large peptide libraries can be combinatorially synthesized make them attractive drug targets. The screening of peptide combinatorial libraries has led to the identification of many biologically-active lead compounds. However, the therapeutic application of peptides is limited by their poor stability and bioavailability in vivo. Therefore, there is a need to synthesize and screen compounds which can maintain high affinity and specificity toward biological receptors but which have improved pharmacological properties relative to peptides.
Combinatorial approaches have recently been extended to xe2x80x9corganic,xe2x80x9d or non-peptide, libraries. The organic libraries, however, are of limited diversity and generally relate to peptidomimetic compounds; in other words, organic molecules that retain peptide chain pharmacophore groups similar to those present in the corresponding peptide. Although the present invention is principally derived from the synthesis of dipeptides, the dipeptides are substantially modified. In short, they are chemically modified through acylation, reduction, and cyclization into the subject bicyclic guanidines, thus providing mixtures and individual compounds of substantial diversity.
Significantly, many biologically active compounds contain guanidine functionalities. Guanidine-containing compounds have been reported to be useful as having hypotensive and adrenergic blocking effects as described, for example, in E. J. Corey and Mitsuaki Ohtani, Tetrahedron Letters., 30(39):5227-5230 (1989). Guanidine-containing compounds also can be used as sweeteners as described, for instance, in Nagarajan et al. Synthetic Communications., 22(8):1191-1198 (1992). Because guanidine moieties are found in many biologically active compounds and are known to have useful therapeutic implications, there is a need to further study and develop large numbers of bicyclic guanidines and their binding to biological receptors.
This invention satisfies these needs and provides related advantages as well. The present invention overcomes the known limitations to classical organic synthesis of guanidine-containing compounds as well as the shortcomings of combinatorial chemistry with small organics or peptidomimetics. Moreover, the present invention provides a large array of diverse bicyclic guanidines which can be screened for biological activity, and as described below, are biologically active.
The invention provides a rapid approach for combinatorial synthesis and screening of combinatorial libraries of bicyclic guanidine compounds. The present invention further provides individual compounds contained within the combinatorial library and methods of using the same, such as for effecting analgesia. More specifically, the present invention relates to the generation of synthetic combinatorial libraries and of organic compounds based on the formula: 
or the formula: 
wherein R1, R2, R3 and R4 have the meanings provided below.